PROJECT SUMMARY: Research Project 2 The African American populations on whom the proposed Research Project (RP) 2 and broader P50 Center focus are disproportionately exposed to social adversities, hardships that take a toll on individuals? biological, neurocognitive, and behavioral systems. During the transition to adulthood, this toll manifests in escalating rates of addictive behavior, including drug use and unhealthy eating. A scientific consensus is emerging that exposure to social adversity and other stressors during childhood and adolescence can promote both drug use and cardiometabolic vulnerabilities through cumulative effects ?under the skin?, including dysregulation of the neuroimmune network (NIN). Despite exposure to chronic stress, however, many African American youth and young adults do not evince NIN dysregulation and vulnerability to drug use and other forms of addictive behavior. In a series of proof-of-principle studies sponsored by our P30 Center, we investigated the long-term effects of participation at age 11 in the Strong African American Families (SAAF) program on individuals when they were transitioning to adulthood (ages 19-25). A number of additional benefits from participation became apparent, many of which involved modifying processes linked to those specified in the NIN framework (i.e., prefrontal-limbic connectivity, limbic region structures, inflammation, and cardiometabolic health). Although provocative findings, data on inflammation and neural activity were collected post hoc, and these findings must be regarded as preliminary until a more rigorous study is performed. The proposed RP2 is designed to meet this need by conducting a randomized controlled trial of the SAAF program (N = 300 low-income families) in which youth will participate in an fMRI assessment and blood draw to index NIN-related neural systems and peripheral inflammation at baseline and a long-term follow-up (2 years). Psychosocial measures from parents and youth will also be conducted at baseline, 1-year, and 2-year follow-up. Our specific aims are to test hypotheses regarding: (1) the influence of participation in SAAF on change in NIN-associated risk markers (neural circuitry subserving threat, reward, and executive control, as well as peripheral inflammation) across 2 years; (2) the mediating role of protective parenting in linking SAAF participation to NIN-associated risk markers; (3) the influence of SAAF on change in addictive behavior vulnerabilities associated with emotion regulation, risky decision making, early-onset substance use, unhealthy eating, and cardiometabolic risk markers; and (4) the mediational chain linking SAAF to addictive behavior vulnerabilities via changes in parenting and NIN-associated risk markers. Testing the experimental effects of SAAF on NIN-specified vulnerability factors with pretest and follow-up fMRI and inflammation assessments represents a dramatic step forward in prevention science, and we hope that RP2 will provide a template for future investigations of drug use prevention programs.